Process for the preparation on 2-aminomethylpyridine derivatives

ABSTRACT

The present invention relates to a novel process for the preparation of 2-amino-methylpyridine derivatives of the formula (I), comprising reacting in a first step 2-substituted pyridine derivatives of the formula (II), with a nitroalkane of the formula (III), in the presence of a base resulting in 2-nitromethylpyridine derivatives of the formula (IV) and hydrogenating these 2-nitromethylpyridine derivatives of the formula (IV) in a second step in the presence of a catalyst and in the presence of an acid, where in the formulae n, X, Y, R 1 , R 2  and A are as defined in the description.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a 35 U.S.C. § 371 national phase conversionof PCT/EP 2004/006075, filed April 26, 2004, which claims priority of GBApplication No. 0309631.0 filed Apr. 28, 2003.

The present invention relates to a novel process for the preparation of2-amino-methylpyridine derivatives which are useful as intermediates forthe preparation of pesticides, by condensing a halogenopyridinederivative with nitromethane and subsequent catalytic hydrogenation ofthe resulting 2-nitromethylpyridine derivatives.

A condensation reaction of nitroethane with electron acceptorsubstituted halogenobenzene has been already disclosed (TetrahedronLett. 1990, 31, 1093-1096). The reduction of an aliphatic nitro group isa widely known reaction (cf. J. Org. Chem. 1993, 58, 2302: reductionwith palladium/carbon and hydrogen in diethyl ether, cf. TetrahedronLett. 1989, 30, 731: reduction with Raney nickel and hydrogen, cf. J.Org. Chem. 1986, 51, 4856: reduction with sodium borohydride andcatalytic nickel chloride hexahydrate, cf. J. Org. Chem. 1990, 55, 4474:reduction with lithium aluminium hydride, cf. Org. Syn. Coll. 1943, 2,617: reduction with tin in hydrochloric acid, cf. J. Am. Chem. Soc.1951, 73, 1293: reduction with iron in hydrochloric acid, cf. WO02/055476: reduction with hydrogen or hydrogen-containing gas mixturesin the presence of a shaped Raney catalyst).

When the nitromethylpyridine is substituted by an additional halogenatom the difficulty exists to avoid the hydrogenolytic dehalogenation ofthe pyridine ring during the reduction step (P. N. Rylander,Hydrogenation Methods, Best Synthetic Series, Academic Press, 1985, page148). Therefore, the above mentioned methods in general cannot beregarded to be applicable to halogen substituted nitromethylpyridinederivatives without significant further improvements.

We have now found a process to prepare 2-aminomethylpyridine derivativeswhich does not possess the above mentioned drawbacks, since only tracesof dehalogenated product is observed, and which therefore is applicableto industrial scale process.

Accordingly, the present invention relates to a process for thepreparation of 2-aminomethylpyridine derivatives of general formula (I)or a salts thereof

in which

-   n represents 0, 1, 2 or 3,-   X represents a halogen atom,-   Y represents a halogen atom, halogenoalkyl, alkoxycarbonyl or    alkylsulphonyl, where Y may be identical or different, if n    represents 2 or 3,-   R¹ represents hydrogen, alkyl, cycloalkyl or cycloalkylmethyl,-   R² represents hydrogen or alkyl,-   R¹ and R² furthermore together represent alkylene,    comprising reacting in a first step 2-substituted pyridine    derivatives of the formula (II)

in which

-   n, X and Y are as defined above and-   A represents a halogen atom, trifluoromethylsulphonyl or    methylsulphonyl or any other radical which may act as a negatively    charged leaving group,    with a nitroalkane of the formula (III)

in which

-   R¹ and R² are as defined above,-   in the presence of a base-   resulting in 2-nitromethylpyridine derivatives of the formula (IV)

in which

-   n, X, Y, R¹ and R² are as defined above,    and hydrogenating these 2-nitromethylpyridine derivatives of the    formula (IV) in a second step in the presence of a catalyst and in    the presence of an acid.

The formula (II) provides a general definition of the 2-substitutedpyridine derivatives required as starting material for carrying out thefirst step of the process according to the invention.

Preferred definitions of the radicals of the 2-substituted pyridinederivatives of the formula (II) are given in the following.

-   n preferably represents 0, 1 or 2, particularly preferably    represents 0 or 1, very particularly preferably represents 1.-   X preferably represents fluorine, chlorine or bromine, particularly    preferably represents fluorine or chlorine, very particularly    preferably represents chlorine.-   X preferably is located in the 3-position of the pyridine ring, i.e.    in ortho position to the radical A.-   Y preferably represents fluorine, chlorine, bromine,    C₁-C₆-halogenoalkyl having 1 to 13 halogen atoms selected from the    group consisting of fluorine, chlorine and bromine,    (C₁-C₆-alkoxy)carbonyl or C₁-C₆-alkylsulphonyl, particularly    preferably represents fluorine, chlorine, bromine,    C₁-C₄-halogenoalkyl having 1 to 9 halogen atoms selected from the    group consisting of fluorine, chlorine and bromine,    (C₁-C₄-alkoxy)carbonyl or C₁-C₄-alkylsulphonyl, very particularly    preferably represents chlorine, trifluoromethyl, trichloromethyl,    methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,    iso-propoxycarbonyl, methylsulphonyl or ethylsulphonyl.-   Y preferably is located in the 5-position of the pyridine ring when    n is 1, i.e. in para position to the radical A.-   A preferably represents fluorine, chlorine, bromine,    trifluoromethylsulphonyl or methylsulphonyl, or any other radical    which may act as a negatively charged leaving group, particularly    preferably represents chlorine, bromine or trifluoromethylsulphonyl,    very particularly preferably represents chlorine.

Preferred starting material of the formula (II) are 2-substitutedpyridine derivatives, in which n is 1, X is chlorine, Y isC₁-C₄-halogenoalkyl, in particular trifluoromethyl, and A is chlorine ortrifluoromethylsulphonyl, in particular chlorine.

The particularly preferred 2-substituted pyridine derivative of formula(II) used as starting material for the process according to theinvention is 2,3-dichloro-5-(trifluoromethyl)pyridine.

2-Substituted pyridine derivatives of the formula. (II) are known and/orcan be prepared according to known methods.

The formula (III) provides a general definition of the nitroalkanesrequired as starting material for carrying out the first step of theprocess according to the invention.

Preferred definitions of the radicals of the nitroalkanes of the formula(III) are given in the following.

-   R¹ preferably represents hydrogen, C₁-C₆-alkyl, C₃-C₈-cycloalkyl or    (C₃-C₈-cycloalkyl)methyl, particularly preferably represents    hydrogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl or (C₃-C₆-cycloalkyl)methyl,    very particularly preferably represents hydrogen, methyl, ethyl,    n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,    n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, iso-hexyl, neo-hexyl,    cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,    cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.-   R² preferably represents hydrogen or C₁-C₆-alkyl, particularly    preferably represents hydrogen, methyl, ethyl, n-propyl, iso-propyl,    n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,    neo-pentyl, n-hexyl, iso-hexyl, neo-hexyl, very particularly    preferably represents hydrogen, methyl, ethyl, n-propyl, iso-propyl,    n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl or    iso-hexyl.-   R¹ and R² furthermore together preferably represent C₂-C₅-alkylene,    particularly preferably represent —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,    —(CH₂)₅—.

Nitroalkanes of the formula (III) are known chemical substances. Typicalexamples for nitroalkanes of the formula (III) are: nitromethane,nitroethane, 1-, 2-nitropropane, 2-nitropropane, 1-, 2-, 3-,4-nitrobutane, 2-methyl-1-nitropropane, nitrocyclopropane,nitrocyclobutane, nitrocyclopentane, nitrocyclohexane,nitromethylcyclopropane. This list only exemplifies nitroalkanes of theformula (III) and does not limit the scope of the present invention.

The formula (IV) provides a general definition of the2-nitromethylpyridine derivatives of the formula (IV) required asstarting material for carrying out the second step of the processaccording to the invention.

The same preferred, particularly preferred and very particularlypreferred definitions as given above for the formulae (II) and (III)apply for the radicals of the 2-nitromethylpyridine derivatives of theformula (IV).

2-Nitromethylpyridine derivatives of the formula (IV) are novel and alsopart of this invention.

Saturated or unsaturated hydrocarbon radicals, e.g. alkyl and alkenyl,can in each case be straight-chain or branched as far as this ispossible, including in combination with heteroatoms, e.g. in alkoxy.

The process according to the present invention is particularly suitablefor the preparation of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine,by reaction of in the first step 2,3-dichloro-5-trifluoromethylpyridinewith nitromethane in the presence of potassium tert-butanolate, sodiumtert-butanolate, or potassium hydroxide in DMSO as diluent to give3-chloro-2-nitromethyl-5-trifluoromethylpyridine, which in the secondstep is hydrogenated in hydrochloric acid using palladium on carbon ascatalyst to yield 3-chloro-2-aminomethyl-5-trifluoromethylpyridine.

The first step of the process according to the present invention iscarried out in the presence of a base. Suitable bases are in each caseall inorganic and organic bases which are customary for such reactions.Preference is given to using alkaline earth metal or alkali metalalkoxides, such as sodium methanolate, sodium ethanolate, potassiumtert-butanolate and sodium iso-butanolate, alkali metal and alkalineearth metal hydroxides, such as sodium hydroxide, calcium hydroxide orpotassium hydroxide, alkali metal carbonates or hydrogencarbonates, suchas sodium carbonate, potassium carbonate, lithium carbonate, caesiumcarbonate, potassium bicarbonate, sodium bicarbonate, and also tertiaryamines, such as trimethylamine, triethylamine, tributylamine,diisopropylethylamine, N,N-dimethylaniline, pyridine,N-methylpiperidine, N,N-dimethylaminopyridine, diazabicyclooctane(DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).Particular preference is given to sodium methanolate, sodium ethanolate,potassium tert-butanolate, sodium tert-butanolate, sodiumiso-butanolate, sodium hydroxide and potassium hydroxide, veryparticular potassium tert-butanolate, sodium tert-butanolate, sodiumhydroxide and potassium hydroxide.

The first step of the process according to the present invention isoptionally carried out in the presence of a diluent. Suitable diluentsare in each case all customary inert organic solvents. Preference isgiven to using optionally halogenated aliphatic, alicyclic or aromatichydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane,methylcyclohexane, benzene, toluene, xylene or decaline; chlorobenzene,dichlorobenzene, dichloromethane; ethers, such as diethyl ether,diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether,dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane oranisole; alcohols, such as methanol, ethanol, tert- and iso-butanol;nitriles, such as acetonitrile, propionitrile, n- or iso-butyronitrileor benzonitrile; amides, such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone orhexamethylphosphoric triamide; esters, such as methyl acetate or ethylacetate; sulphoxides, such as dimethyl sulphoxide; or sulphones, such assulpholane.

The reaction temperatures employed to the first step of the reactionaccording to the invention may be varied over a broad range. In generalthe reaction is carried out between −20° C. and +150° C., preferablybetween 0° C. and 60° C., particularly preferably between 20° C. and 30°C.

The first step of the reaction is expediently carried out underatmospheric pressure, although it is also possible to work under reducedor elevated pressure. Particular preference is given to carrying out thereaction under atmospheric pressure.

The reaction time of the first step can be different depending on thescale of the reaction and may vary between 1 h and 48 h, preferablybetween 3 h and 24 h, particularly preferably between 5 h and 15 h.

The first step of the process is carried out in practice by reacting,for example, 1 mol of a 2-substituted pyridine derivative of formula(II) with between 1 and 10 mol, preferably between 1 and 5 mol,particularly preferably between 1 and 3 mol of the nitroalkane of theformula (III) in the presence of between 1 and 10 mol, preferablybetween 1 and 5 mol, particularly preferably between 1 and 3 mol of abase. In certain cases also other ratios may be applicable.

The second step of the process according to the invention is carried outin the presence of a catalyst. Suitable catalysts to be mentioned areRaney nickel, Raney cobalt, palladium on carbon, palladium salts,platinum and platinum oxides. Preference is given to Raney nickel, Raneycobalt and palladium on carbon. In particular palladium on carbon isused in a range of between 0.0001 to 2 equivalents of the2-nitromethylpyridine derivative of the formula (IV). Ammonium chloridemay be used as co-catalyst in a range of between 0 and 10 equivalents.To minimize dehalogenation, it might be beneficial to add a catalystinhibitor (e.g. KBr) (cf. WO 02/16322)

The catalyst may be recycled according to methods well known by the manordinary skilled in the art. Particularly, the catalyst may be easilyrecycled by filtration.

The second step of the process according to the present invention iscarried out in the presence of an acid. Suitable acids are in each caseall inorganic and organic acids which are customary for such reactions.Preference is given to using mineralic acids, such as hydrochloric,sulphuric and phoshoric acid; organic acids, such as formic, acetic,propionic, trifluoroacetic, trichloroacetic and methanesulphonic acid.Particularly hydrochloric or acetic acid are used.

The second step of the process according to the present invention isoptionally carried out in the presence of a diluent. Suitable diluentsare in each case all customary organic solvents. Preference is given tousing optionally halogenated aliphatic, alicyclic or aromatichydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane,methylcyclohexane, benzene, toluene, xylene or decaline; chlorobenzene,dichlorobenzene, dichloromethane; ethers, such as diethyl ether,diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether,dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane oranisole; alcohols, such as methanol, ethanol, tert- and iso-butanol;amides, such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylformanilide, N-methylpyrrolidone or hexamethylphosphorictriamide; esters, such as methyl acetate or ethyl acetate; organic acidssuch as acetic acid.

The reaction temperatures employed to the second step of the reactionaccording to the invention may be varied over a broad range. In generalthe reaction is carried out between −20° C. and +150° C., preferablybetween 0° C. and 60° C., particularly preferably between 20° C. and 30°C.

The second step of the reaction is carried out under a hydrogen pressureof between 0.5 and 200 bar, preferably of between 2 and 50 bar,particularly preferably of between 3 and 10 bar.

The reaction time of the second step can be different depending on thescale of the reaction and may vary between 1 h and 48 h, preferablybetween 3 h and 26 h.

The second step of the process is carried out in practice byhydrogenating, for example, 1 mol of a 2-nitromethylpyridine derivativeof the formula (IV) in the presence of a catalyst and in the presence ofan acid in an amount of between 0 and 10 mol, preferably between 1 and 5mol, particularly preferably between 2 and 3 mol.

The process according to the present invention will now be illustratedwith reference to the following example.

PREPARATION EXAMPLES Example 1(3-chloro-2-nitromethyl-5-trifluoromethylpyridine)

Potassium tert.-butanolate (20.2 g, 0.18 mol, 2 eq.) is placed togetherwith 90 ml dry dimethyl sulphoxide in a 250 ml three-necked-bottle.Under dry argon atmosphere the nitromethane (11 g, 0.18 mol, 2 eq.) isadded slowly with mechanical stirring while cooling with an ice bath.Stirring of the reaction mixture at 20° C. is continued for additional15 min. Then 2,3-dichloro-5-trifluoromethylpyridine (19.44 g, 0.09 mol,1 eq.) is added within 5 min at 17° C. The temperature first drops to13° C., while at the end of the addition an exothermic reaction to 27°C. is observed. The mixture is allowed to cool to room temperature andstirring is continued for additional 14 h.

The dark brown crude product is poured into 150 ml of water, followed bythree extractions with 50 ml ethyl acetate each. The combined organiclayers are washed with three 30 ml portions of water and aresubsequently dried over anhydrous sodium sulphate. After filtration thesolvent is removed at 20° C. and under 150 mbar reduced pressure.

Yield: 22.8 g 3-chloro-2-nitromethyl-5-trifluoromethylpyridine (95.7%theoretical yield, 90.9% purity)

¹H NMR (d₆-DMSO): δ=6.21 (s, 2H), 8.68 (d, 1H), 9.05 (dd, 1H) ppm.

MS (LC/MS-coupling): m/z (%)=243 (36) and 241 (100) each [M⁺+H].

Example 2 (3-chloro-2-nitromethyl-5-trifluoromethylpyridine PyMN)

Powdered potassium hydroxide (9.35 g, 0.15 mol, 3 eq.) is placedtogether with 70 ml dry DMSO in a 250 ml three-necked-bottom and underdry argon atmosphere the nitromethane (6.1 g, 0.1 mol, 2 eq) solved in30 ml dry DMSO is added within 30 min slowly with mechanical stirringwhile cooling with an ice bath to maintain the temperature at 20° C.Stirring of the reaction mixture at 20° C. is continued for additional15 min. Then 2,3-dichloro-5-trifluoromethylpyridine (10.80 g, 0.05 mol,1 eq.) is added as one portion without endo- or exothermic reaction. Themixture is heated to 50° C., stirred for 3 h at this temperature andthen allowed to cool to room temperature.

The dark brown crude product is poured into 500 ml of water, acidifiedby addition of diluted hydrochloric acid and followed by threeextractions with 50 ml ethyl acetate each. The combined organic layersare washed with three 30 ml portions of water and are subsequently driedover anhydrous sodium sulphate. After filtration the solvent is removedat 20° C. and under 150 mbar reduced pressure.

Yield: 9.72 g 3-chloro-2-nitromethyl-5-trifluoromethylpyridine (73.9%theoretical yield, 91.4% purity)

Example 3 (3-chloro-2-aminomethyl-5-trifluoromethylpyridinehydrochloride)

A solution of 7.69 g (0.211 mol, 2 eq.) hydrogen chloride in drymethanol is prepared by dilution of 30% methanolic HCl with theappropriate amount of methanol.3-chloro-2-nitromethyl-5-trifluoromethylpyridine (25.9 g, 0.106 mol, 1eq.) and 5.50 g 5% Pd on carbon are placed together with the methanolicHCl obtained above in a hastelloy autoclave and the reduction is carriedout under 5 bar hydrogen pressure for 26 h at room temperature.

After pressure regulation to 1 bar the catalyst is removed by filtrationand after washing with small amounts of methanol all organic phases werecombined and the solvent is removed at 30° C. and under 150 mbar reducedpressure.

The crude crystals obtained are suspended in dichloromethane forpurification. After filtration and washing with dichloromethane the palegrey crystals are dried over phosphorous pentoxide.

Yield: 24.13 g 3-chloro-2-aminomethyl-5-trifluoromethylpyridinehydrochloride (92.5% theoretical yield, 99.9% purity

¹H NMR (d₆-DMSO): δ=4.37 (d, 2H), 8.61 (d, 1H), 8.83 (s broad, 3H), 9.03(d, 1H) ppm.

MS (GC/MS-coupling): m/z (%)=212 (13) and 210 (38) each [M⁺], 184 (24)and 182 (79), 30 (100).

1. A process for the preparation of 2-aminomethylpyridine derivatives of formula (I) or salts thereof

comprising the steps of reacting 2-substituted pyridine derivatives of the formula (II)

with a nitroalkane of the formula (III)

in the presence of a base resulting in 2-nitromethylpyridine derivatives of the formula (IV)

and then hydrogenating these 2-nitromethylpyridine derivatives of the formula (IV) in the presence of a catalyst and an acid, wherein n represents 0, 1, 2 or 3, X represents a halogen atom, Y is selected from the group consisting of a halogen atom, halogenoalkyl, alkoxycarbonyl, and alkylsulfonyl, where each Y may be identical or different if n represents, 2 or 3, R¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and cycloalkylmethyl, R² is selected from the group consisting of hydrogen and alkyl, or R¹ and R² taken together can represent alkylene, and A is selected from the group consisting of halogen, trifluoromethylsulfonyl methylsulphonyl, and other radicals that can act as negatively charged leaving groups.
 2. The process of claim 1, where the base is selected from the group consisting of sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium tert-butanolate, sodium iso-butanolate, sodium hydroxide, and potassium hydroxide.
 3. The process of claim 1 wherein the catalyst is selected from the group consisting of Raney nickel, Raney cobalt, and palladium on carbon.
 4. The process of claim 1 wherein the acid is selected from the group consisting of hydrochloric, sulphuric, phosphoric, formic, acetic, propionic, trifluoroacetic, trichloroacetic, and methanesulphonic acids.
 5. The process of claim 1 wherein the 2-aminomethylpyridine derivative of formula (I) is 3-chloro-2-nitromethyl-5-trifluoromethylpyridine, the 2-substituted pyridine derivative of the formula (II) is 2,3-dichloro-5-trifluoromethylpyridine, the nitroalkane of the formula (III) is nitromethane, and the 2-nitromethylpyridine derivative of the formula (IV) is 3-chloro-2-nitromethyl-5-trifluoromethylpyridine.
 6. The process of claim 5 wherein the base is selected from the group consisting of potassium tert-butanolate and potassium hydroxide.
 7. The process of claim 5 wherein the acid is hydrogen chloride.
 8. The process of claim 6 wherein the acid is hydrogen chloride.
 9. The process of claim 5 wherein the catalyst is palladium on carbon.
 10. The process of claim 6 wherein the catalyst is palladium on carbon.
 11. The process of claim 7 wherein the catalyst is palladium on carbon.
 12. The process of claim 8 wherein the catalyst is palladium on carbon. 